The broad goals of this proposal are to develop enhanced understanding of how the progressive loss of kidney function leads to increased oxidative stress, inflammation, and accelerated development of cardiovascular disease. The long-term objective of this proposal is to develop the data critical for a subsequent large scale, multicenter, randomized, controlled trial designed to alleviate oxidative stress, reduce inflammation, and reduce cardiovascular morbidity in patients with chronic kidney disease. Currently, both the incidence and prevalence of chronic kidney disease leading to end-stage renal disease continue to increase at an alarming rate in the United States. According to the United States Renal Data System, in 2000 there are 370,000 prevalent ESRD patients, which are expected to grow to 610,000 by the year 2010. Furthermore, the adjusted death rate for all incident ESRD patients was 19.8 per 100 patient years at risk, with cardiovascular disease accounting for more than 50 percent of mortality in this patient population. Recent analyses demonstrate that there are at least 10.9 million people in the United States with chronic kidney disease and that for this population, there are substantially increased cardiovascular risks, prompting the Surgeon General to include chronic kidney disease s a focus area for improving the nation's health in Healthy People 2010. The metabolic derangements accompanying progressive loss of kidney function lead to unique patterns of oxidative injury specific to the uremic state. For patients with chronic kidney disease, non-traditional risk factors for cardiovascular disease such as increased oxidative stress and inflammation may be especially important. The aims of this proposal are to determine, in a prospective study, how progressive loss of kidney function influences oxidative stress, inflammation, and cardiovascular disease, and how oxidative stress, inflammation, and endothelial dysfunction are interrelated. A further aim is to determine in the longitudinal study is to determine the extent to which increased oxidative stress and inflammation are risk factors for cardiovascular disease events in patients with chronic kidney disease. An additional aim is to determine the effects of antioxidant therapy on biomarkers of oxidative stress, markers of inflammation and endothelium-dependent vascular function in patients with chronic kidney disease. This proposal incorporates a series of observational and interventlonal studies measuring the extent of cardiovascular disease with extensive ex vlvo measures of biomarkers of oxidative stress and inflammation in patients with chronic kidney disease. Coordination between the clinical data and the ex vivo studies will be emphasized to achieve maximal understanding of the pathophysiology of uremic cardiovascular disease.